Cetuximab With or Without Brivanib in Treating Patients With K-Ras Wild Type Tumours and Metastatic Colorectal Cancer

A Phase III Randomized Study of Brivanib Alaninate (BMS-582664) in Combination With Cetuximab (Erbitux®) Versus Placebo in Combination With Cetuximab (Erbitux®) in Patients With K-RAS Wild Type Tumors Previously Treated With Combination Chemotherapy for Metastatic Colorectal Carcinoma

RATIONALE: Brivanib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. Monoclonal antibodies, such as cetuximab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. It is not yet known whether giving brivanib together with cetuximab is more effective than cetuximab alone in treating patients with metastatic colorectal cancer.

PURPOSE: This randomized phase III trial is studying cetuximab to see how well it works compared with cetuximab given together with brivanib in treating patients with metastatic colorectal cancer.

OBJECTIVES:

Primary

• To compare the overall survival of patients with previously treated K-Ras wild type metastatic colorectal carcinoma treated with brivanib alaninate in combination with cetuximab versus placebo in combination with cetuximab.

Secondary

• To compare the progression-free survival of these patients.
• To compare the objective response rate and duration of response in these patients.
• To compare the quality of life of these patients.
• To compare the health utilities of these patients.
• To conduct a comparative economic evaluation of these patients.
• To evaluate the safety profile of this regimen in these patients.
• To explore an association between FGF-2, BRAF mutations, amphiregulin (AREG) and epiregulin (EREG) as determined from paraffin embedded tumor specimens and the potential for clinical benefit from the addition of brivanib alaninate or placebo to cetuximab in terms of overall survival, progression-free survival and objective response rate compared to cetuximab alone.
• To explore associations with mRNA and/or protein expression and/or variations in genes associated with epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), angiogenesis, and other related pathways and the potential for clinical benefit from the addition of brivanib alaninate to cetuximab in terms of overall survival, progression-free survival, and objective response rate compared to cetuximab alone.
• To explore an association with changes of Collagen IV in the blood and the potential for clinical benefit from the addition of brivanib alaninate to cetuximab in terms of overall survival, progression-free survival and objective response rate compared to cetuximab alone.
• To establish a comprehensive tumor bank linked to a clinical database for the further study of molecular markers in colorectal cancer.

OUTLINE: This is a multicenter study. Patients are stratified according to participating center and ECOG performance status (0-1 vs 2). Patients are randomized to 1 of 2 arms.

• Arm I: Patients receive oral brivanib alaninate once daily and cetuximab IV over 60-120 minutes once weekly.
• Arm II: Patients receive oral placebo once daily and cetuximab IV over 60-120 minutes once weekly.

In both arms, treatment continues in the absence of disease progression or unacceptable toxicity.

Tumor tissue and blood samples are collected for correlative studies. Samples are analyzed for biomarker levels (Collagen IV, FGF-2, and epiregulin, amphiregulin, and BRAF mutation status) and correlation with response.

After completion of study treatment, patients are followed at 4 weeks and then every 8 weeks thereafter.

DISEASE CHARACTERISTICS:

• Histologically confirmed primary colorectal cancer

  • Metastatic disease

• Tumor must be confirmed to be K-Ras wild type (i.e., No K-Ras mutation found) by means of mutation analysis performed on representative samples of diagnostic tumor tissue by a central reference laboratory (archival tumor samples are acceptable for K-Ras mutation analysis)

• Must have received a prior thymidylate synthase inhibitor (e.g., fluorouracil, capecitabine, raltitrexed, or tegafur-uracil) for adjuvant and/or metastatic disease

  • Thymidylate synthase inhibitor may have been given in combination with oxaliplatin or irinotecan hydrochloride

• Must meet one of the following criteria:

  • Received and failed* an irinotecan hydrochloride-containing regimen (i.e., single-agent or in combination) for treatment of metastatic disease
  • Relapsed within 6 months of completion of an irinotecan hydrochloride-containing adjuvant therapy
  • Has documented unsuitability** for an irinotecan hydrochloride-containing regimen NOTE: *Failure is defined as either progression of disease or intolerance to the irinotecan-containing regimen, where intolerance is defined as discontinuation due to any of the following: severe allergic reaction or delayed recovery from toxicity preventing retreatment NOTE: **Documented unsuitability for irinotecan includes known hypersensitivity to irinotecan, abnormal glucuronidation of bilirubin, Gilbert's syndrome, previous pelvic/abdominal irradiation, or elderly with comorbid conditions

• Must meet one of the following:

  • Received and failed* an oxaliplatin-containing regimen (i.e. single-agent or in combination) for treatment of metastatic disease
  • Relapsed within 6 months of completion of an oxaliplatin containing adjuvant therapy
  • Has documented unsuitability** for an oxaliplatin-containing regimen NOTE: *Failure is defined as either progression of disease or intolerance to the oxaliplatin-containing regimen, where intolerance is defined as discontinuation due to any of the following: severe allergic reaction, persistent severe neurotoxicity or delayed recovery from toxicity preventing retreatment

NOTE: **Documented unsuitability for oxaliplatin includes known hypersensitivity to oxaliplatin or other platinum compounds, pre-existing renal impairment, or Grade 2 or greater neurosensory neuropathy

• Measurable or evaluable disease

• Patient must consent to provision of, and investigator(s) must confirm access to and agree to submit at the request of the NCIC CTG Central Tumor Bank, a representative formalin fixed paraffin block of tumour tissue

• Patient must consent to provision of a sample of blood

• No symptomatic CNS metastases

  • Patients with signs or symptoms suggestive of brain metastasis are not eligible unless brain metastases are ruled out by CT or MRI scans

PATIENT CHARACTERISTICS:

Inclusion criteria:

• ECOG performance status 0-2
• Absolute granulocyte count ≥ 1.5 x 10^9/L
• Platelet count ≥ 75 x 10^9/L
• Hemoglobin ≥ 80 g/L
• Total bilirubin ≤ 1.5 times upper limit of normal (ULN) (2.0 times ULN with documented liver metastases)
• ALT and AST ≤ 2.5 times ULN (5.0 times ULN with documented liver metastases)
• Serum creatinine ≤ 1.5 times ULN or creatinine clearance > 50 mL/min
• Magnesium > 0.5 mmol/L (1.2 mg/dL)
• LVEF > 45% by ECHO or MUGA scan
• No proteinuria ≥ 2+ on dipstick or ≥ 1 g on 24 hour urine collection
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception prior to, during, and for 12 weeks after completion of study treatment
• Able (i.e., sufficiently fluent) and willing to complete the quality of life (EORTC QLQ-C30 and Skindex-16) and health utilities questionnaires (HUI3) in either English or French

Exclusion criteria:

• A history of other malignancies, except: adequately treated nonmelanoma skin cancer, curatively treated in situ cancer of the cervix, or other solid tumors curatively treated with no evidence of disease for ≥ 5 years

• Any active disease condition which would render the protocol treatment dangerous or impair the ability of the patient to receive protocol therapy

• Any condition (e.g., psychological, geographical, etc.) that does not permit compliance with the protocol

• Uncontrolled or significant cardiovascular disease including any of the following:

  • Myocardial infarction within 12 months
  • Uncontrolled angina within 6 months
  • Clinically significant congestive heart failure
  • Stroke, transient ischemic attack, or other ischemic event within 12 months
  • Severe cardiac valve dysfunction

• Uncontrolled hypertension (consistent elevation of systolic BP > 150 and diastolic BP > 100 mmHg)

• History of a thromboembolic event in the last 6 months despite being treated with anticoagulation

  • Patients are eligible if they have experienced a thromboembolic event greater than 6 months previously and have initiated and are stable on anticoagulation or if they have previously initiated and are stable on anticoagulation for prevention of thromboembolic events

• Severe restrictive lung disease or radiological pulmonary findings of "interstitial lung disease" on the baseline chest x-ray which, in the opinion of the investigator, represents significant pathology

• Serious non-healing wounds, ulcers, or bone fractures

• History of allergy to brivanib (alaninate or related drug class

• Unable to swallow tablets

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• Adequately recovered from recent surgery, chemotherapy and/or radiation therapy
• At least 4 weeks must have elapsed from major surgery, prior chemotherapy, prior treatment with an investigational agent or prior radiation therapy
• No prior cetuximab or other therapy* with targets the EGFR pathway (e.g., erlotinib hydrochloride, gefitinib hydrochloride, panitumumab)
• May have received a single prior regimen which targets the VEGFR pathway (e.g., bevacizumab , vatalanib, AZD2171, sorafenib tosylate, sunitinib malate, or others)
• No prior murine monoclonal antibody therapy (e.g., edrecolomab)
• No other concurrent chemotherapy
• No other concurrent therapies targeting the EGFR pathway (e.g., erlotinib, gefitinib, panitumumab, or others) or other therapies targeting the VEGFR pathway (e.g., bevacizumab , vatalanib, AZD2171, sorafenib tosylate, sunitinib malate, or others)
• Concurrent antihypertensive therapies allowed
• Concurrent aspirin allowed
• No other concurrent noncytotoxic experimental agents